Human papillomavirus (HPV)-immortalized cervical epithelial cells and HPV-positive cervical carcinomas are being evaluated as a model of lymphokine modulation of epithelial cell sensitivity to natural immunologic cytotoxicity. Epithelial cells, immortalized by transfection with HPV-16 DNA, are treated with 2.5 U/ml leukoregulin for 1 hr and mixed with natural killer (NK) cells or interleukin 2 (IL2)-induced lymphokine activated killer (LAK) cells at E:T ratios up to 50:1.in a 4 hr 51 Cr release assay. Transfected exocervical cells are evaluated at early and late passages to determine stages at which they can be destroyed by NK and/or LAK cell cytotoxicity. Both early and late passage HPV-16- immortalized cells are resistant to NK but sensitive to LAK cell cytotoxicity. Leukoregulin treatment of the target cells induces a modest sensitivity to NK (p<.05) and markedly up-regulates LAK sensitivity 1.5 to fourfold. QG-U and C4-1 cervical carcinoma cells possessing integrated HPV-16 and HPV-18 DNA, respectively, are resistant to NK but sensitive to LAK. The response of leukoregulin-treated QG-U and C4-1 cells is similar to HPV-16- immortalized targets, i.e., leukoregulin confers sensitivity to the once NK-resistant tumor target cells and dramatically increases their sensitivity to LAK. Although the HPV-immortalized exocervical cells containing integrated HPV DNA are not yet tumorigenic, they mimic the response of established HPV-16 or -18- positive cervical carcinoma cells. These observations provide a foundation for the usefulness of this model in evaluating the therapeutic potential of leukoregulin alone, or in combination with other cytokines or chemotherapeutic drugs in the prevention and treatment of cervical dysplasia and neoplasia.